The liver plays a critical role in maintaining whole body glucose homeostasis. A major cause of hyperglycemia in Type 2 diabetic patients is the inability of the liver to respond to a signal from insulin to inhibit production of glucose via gluconeogenesis. KLF15 (Kruppel-like factor 15) is a transcription factor involved in the control of both hepatic insulin sensitivity and gluconeogenesis. The specific aims of this proposal are designed to elucidate the mechanism by which KLF15 regulates hepatic glucose production. KLF15 is highly expressed in the liver, and mice lacking KLF15 (KLF15-/- mice) exhibit severe hypoglycemia after an overnight fast. The mRNA expression levels of multiple amino acid degrading enzymes are markedly reduced in KLF15-/- mice. As a result, amino acid catabolism is impaired, and this has been shown to promote fasting hypoglycemia in KLF15-/- mice by limiting the availability of gluconeogenic substrate. Thus, KLF15 is required for efficient gluconeogenesis. KLF15-/- mice also exhibit hepatic insulin sensitivity, as shown in hyperinsulinemic-euglycemic clamp studies. These in vivo observations support the conclusion that KLF15 is a positive regulator of hepatic glucose production. Further evidence for this conclusion is that hepatocytes isolated from KLF15-/- mice produce less glucose than WT hepatocytes, while adenoviral overexpression of KLF15 rescues deficient glucose production in KLF15-/- hepatocytes and increases glucose production in WT hepatocytes. Finally, KLF15-/- mice are protected against high-fat feeding induced insulin resistance, suggesting a critical role for KLF15 in the development of diabetes. The goals of this project are: 1) to test the hypothesis that KLF15 regulates the hepatic response to insulin by controlling the rate of gluconeogenesis, 2) to elucidate a specific mechanism of regulation of hepatic insulin sensitivity by KLF15, and 3) to understand the mechanism by which KLF15 regulates the expression of amino acid degrading enzymes. Understanding the fundamental mechanisms involved in the regulation of hepatic glucose production is likely to provide the basis for improved therapies for diabetes. PUBLIC HEALTH RELEVANCE: Kruppel-like factor 15 (KLF15) plays an important role in the liver as a regulator of gluconeogenesis and hepatic insulin sensitivity. Studying the mechanism by which KLF15 controls hepatic glucose production and whole-body glucose homeostasis may lead to new therapies for the treatment of metabolic disorders such as diabetes.